Alveolar macrophages (mphi) are a crucial element of the host defense response. Nonetheless, the factors that modulate and regulate their effector functions (e.g., scavenger and secretion activities) are unclear. Our current studies show that the functions of alveolar (mphi) are selectively pH-sensitive. As such, alterations in intracellular pH (pHi) due to endogenous (e.g., increased cellular metabolism during mphi activation) or exogenous factors (e.g., pathologic changes in mphi microenvironment) can have profound effects on mphi competence. Mphi pHi is determined by the balance between processes that generate intracellular acid-base equivalents and membrane transporters that regulate the efflux of such equivalents. We have identified the major acid-base transporters in alveolar mphi: electrogenic plasmalemma V-type H+-ATPase and electroneutral exchangers (Na+/H+ and C1-/HCO3 ). These transporters link the regulation of mphi pHi, cell volume, and Em. We hypothesize that (1) in resting (unstimulated) mphi pHi and volume are both tightly regulated although with different kinetics, (2) in activated mphi pHi regulation takes precedence over volume regulation such that pHi (and pH-sensitive cell functions) are preserved at the expense of volume homeostasis, and (3) this hierarchy in housekeeping functions has important consequences for mphi activation. Previous efforts to kinetically characterize acid-base transporters have used measurements of pHi recovery from challenges induced with weak base/acid prepulses. Our studies show that this approach leads to erroneous estimates of transport kinetics, with potential errors in data interpretation. We will use tightly-coupled mathematical and experimental studies (incorporating pHi, volume, Em, and plasmalemma ion conductances/fluxes) to overcome this limitation. To test our hypotheses, we propose coupled mathematical/experimental studies to quantify the hierarchy and kinetics of pHi/volume regulation in alveolar mphi (resting or activated) and monocytes, and to determine the interaction of mphi pHi/volume regulation and oxidant production (NO, superoxide, and peroxynitrite). Our findings should provide new fundamental insights into the mechanisms that modulate alveolar mphi functions in health and disease.